Hydrocarbon esters of hydrocarbonylthiolsulfinic acids and their process of preparation



Patented May 23, 1950 HYDROCARBON ESTERS OF HYDROCAR- BONYLTHIOLSULFINIC ACIDS AND THEIR PROCESS OF PREPARATION Chester J. Cavallito and La Verne D. Small, Albany, N. Y., assignors to Sterling Drug Inc., Wilmington, Del., a corporation of Delaware No Drawing. Application December 18, 1946, Serial No. 717,080

Claims. (Cl. 260-453) This invention relates to organic thiolsulfinates and to a method for the preparation thereof.

This application is a continuation-in-part of Preliminary data indicated that allyl disulfide oxide is a member of a new class of organic compounds having the functional grouping SO-S and that it has the structure om=on-cm-s-s-on,-on=cni Although compounds of this type have been postulated as existing as intermediate products in the well-known oxidation of disulfides to yield thiolsulfonates, previous investigators have found that even cautious oxidation of the disulfides yielded no products corresponding to the postulated oxidation stage (Gilman, Organic Chemistry, second edition, vol. I, p. 907). In the course of experiments directed toward the synthesis of members of this new class of compounds, which we have designated as thiolsulfinates, we have synthesized allyl 2-propene-l-thiolsulfinate and have proved its identity with the antibiotic substance, allyl disulfide oxide, obtained from garlic cloves. Further, we have discovered a general method whereby organic thiolsulfinates can be obtained in good yield. Our invention comprises treating an organic disulfide with an organic per-acid, preferably in the presence of a solvent, at a temperature below 55 0., whereby there is produced an organic thiolsulfinate. This oxidation reaction can be expressed by the following equation:

wherein R1, R2, R, and R each represent organic the starting materials in the process of our invention can be of the most varied type where R1 and R2 can each be either aliphatic-type or aromatic-type radicals or where R1 and R2 taken together constitute a bivalent radical such as alkylene. By the terms aliphatic-type and aromatic-type radicals, we mean to include: (41) alkyl radicals, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, sec-butyl, n-amyl, etc., (b) alkenyl radicals, for example, allyl, methallyl, etc., (0) aralkyl radicals, for example, benzyl, phenethyl, etc., (d) alicyclic radicals, for example, cyclohexyl, cyclopentyl, cyclohexenyl, etc., (e) saturated heteryl radicals, for example, piperidyl, morpholinyl, tetrahydropyranyl, etc., and (f) aromatic-type heteryl radicals such as pyrldyl, thiazyl, furyl, thienyl, pyrimidyl, quinolyl, etc. which have a conjugated system of double bonds, and (g) aryl radicals, for example, phenyl, naphthyl, etc.

The afore-mentioned radicals can be unsubstituted or can bear one or more functional groups such as hydroxyl, carbonyl, halogen, carboxyl, amino, cyano, ether, etc.

Under the oxidation conditions employed in our process, mercaptans are converted to disulfides which in turn are converted, in the presence of a sufficient quantity of the organic per-acid, to thiolsulfinates. Although this procedure may offer some advantages in specific instances, we have found that, in general, better yields of the desired thiolsulfinates are obtained by the direct use of the appropriate disulfide as the starting material than by the use of a procedure involving intermediate formation of the disulfide in the reaction mixture.

As the organic per-acid which is employed as the oxidizing agent in our process, there can be used, for example, perbenzoic acid, perphthalic acid, perfuroic acid, percamphoric acid, peracetic acid, etc. For reasons of economy and ease of availability, We prefer to use perbenzoic acid or perphthalic acid. In some instances the use of a particular per-acid will be found to afford a somewhat better yield of thiolsulfinate than that obtained by using another per-acid, e. g. in converting isopropyl disulfide to isopropyl 2-propanethiolsulfinate, peracetic acid is preferable to perbenzoic acid. We have found that in order to obtain a satisfactory yield of the thiolsulfinate, the molecular ratio of oxidizing agent, i. e. organic per-acid to disulfide, should be within the range 0.5-2.0, the optimum ratio being about 1. It is understood, of course, that if the starting material contains one or more functional groups variety of organic liquids can be employed with out significant effect on the yieldof thiolsulfinate, for example: halogenated hydrocarbons, alcohols, lower fatty acids, nitriles, ketones, esters, etc. This group includes, forexample.

benzene, petroleum ether, chloroform,"methylenechloride, carbon tetrachloride, ethyl alcohol, t-butyl alcohol, acetic acid, acetonitrile; acetone, and ethyl acetate.

The reaction should be conducted at a temperature below 55 (3., since the yield of thiolsulfinate drops off markedly above thispoint. -We prefer toconductthe reaction, for l'lie'purpose of convenience, 'at about -35? 0., i but satisfactory yieldsare also obtained at-niuch lowertempera tures, for examplegat 2Q C.

The oxidation. process generally proceeds quickly, the reaction time being about 3!) minsr d h yield vis bta iered i hifiq t y y extending the period of contact of the reactants to -three hours. However; in some instances; as

inthe conversion of bis(secondary alkyl) disulfidesto thiolsulfinates; e.- g. preparation of isopropyl z-propanethiolsulfi-nate from isopropyl disulfide, steric hindrance is apparently an important factor and we have found that it is advantageous to irradiate the reaction mixture with ultraviolet light inorder to facilitate reaction insuch-instances. This efiect of steric hindrance is evenmore pronounced'in the case of bis(t ertiary alkyl) disulfides, for example, tertiary hexyli-disulfide and tertiary butyl disulfide. I

Isolation of :the thiolsulfinates obtained by our process is carried out bythe usual procedures of fractional distillation at reduced pressure, partition between solvents, or fractional crystallization. Itisdesirable to employ an isolation procedure which does not require use of temperatures above 55? 0., since in this way loss of prodnot through thermal-decompositoin of the thiolsulfinatesis avoided. In the case Of 3,1ky1 a1- ih ol u fieeies or example w ci to em,- ploy fractional distillation at reduced pressure of the reaction inixture'pflicededby an alkali wash to-remove tracesof unused oxidant and acidic bY-P Q U of h e ctionh rst ra t on of the distillate consist of the organic solvent together with some-unchanged disulfide starting material. Subsequently thedesired thiolsuli'inate fraction distills; leaving as the'distillation residue a small amount of relatively non volatileimpurities; consisting chiefly of higher oxidation prod u'cts such 'a'sthiolsul'fonatesa'n'd disulfons; which are present in thereaction'niixture. The chemical properties of the thiolsuhinates obtained by our process vary considerably: of course, depending onthe natureoffthe radicals a h bbrth linkage. Thiolsulfinates are converted by oxidationto 'thi'ol'sulfonate's, and by reducticn to mer'c'aptans' and disul'fides. 'Under hydrolytic conditions} 'thiolsulfinates 'are transformed todisulfides and 's'u-lfur dioxid roduced? As a class, the thiolsulfinates are relatively stable com= pounds which require no special precautions for their preservation when stored for several weeks at room temperature, although temperatures above 55? C. cause serious decomposition. The compoundallyl 2propene-i--thiols'ulfinate is eX- ceptionally sensitive, however, exhibiting a great tendency to polymerize, at the same time losing its" antibiotic activity, and thus must be stored at low temperature."

The '"alkyl "alka'nethiolsulfinates having 2-12 carbon atoms' are' liquids, being colorless or slightly yellow oils, which have a sharp odor. These'compounds' are more soluble in water than are the corresponding disulfides, the members of the series exhibiting decreasing water solubility as' the number of -carbon atoms increases, the

higher members being practically insoluble. These compounds react with cysteine to form solid condensation products in accordance with the e c fi eiiw; R-fi-S-R zgs cni-onmnikqoon 2 s-s-on,QH Nnz -Co011 1110 The organic thiolsulfinates are'active anti-ban teria-Faii'd"fungicidal agents Which are fictive' against "both' Gram-negative and Gram-positive organisms. This property is inherent in the" S s, ll 0 group, the compounds being inactivated by any reagent-which destroys this functional group.

h n ibioti a t v y exhi it d t w rd. r u

groups of organisms varieswiththe type of radicals attached to the group. Thus, in the alkyl alkanethiolsulfinate series, butyl l-butanethiolsulfinate is more effective than ethyl thanetliiolsulfinate against Gram-positive organisms such-a's' Staph. aureus,"

5.2 g. of allyl disuliide is dissolved in IQOO ml. of chloroform and the: solution is cooled in an ice bath. 'Tothje chilled solution there is slowly added with stirring at scion ot 4.8 g. orp e'r: benaoio acid in llidilml of chloroform." The'reac tion mixture is allowed to stand for about an" hour at room temperature and is then washed" successively with two 250 m1. portions of a 1.0%

aqueous solution of sodium bicarbonate and a ml. portion of water. The chloroform is then distilled from-the chloroform solution at about 30-40 "mm; pressure and the distillation residue istreated with '15 mlrof' petroleum "ether. This mixtureis extracted with six'200-ml; portions of water? The'a'queous extracts are'combined' and extracted with four 50 ml;portions-ofchloroform: The chloroform is distilledirom' the combinedchlorofoim 'extractsat"about"30 40 pressure.

Ihe distillation residue, which is a yellow oil consisting of allyl 2-propene-1-thiolsulfinate, weight 3.15 g. The pure compound has a d4 of 1.112 and 72 1.562. Analysis calcd. for CeHmOSz: C, 44.44%; H, 6.17%. Found for synthetic allyl 2-propene-1-thiolsulfinate: C, 44.82%; H, 6.24%. Physical data and range of.

analytical values found for allyl 2-propene-1-" thiolsulfinate obtained from Allium sati'vum: C, 44.12% to 44.59%; H, 6.30% to 6.34%; d4 1.112 and 1 1.561.

' The synthetic allyl Z-propene-l-thiolsulfinate reacts with l-cysteine hydrochloride to yield a solid condensation product melting at approximately 185 C. (dec.) There is no depression of the melting point when a sample of this condensation product is mixed with the condensation product, M. P. 185 C. (dec.), produced by the interaction of l-cysteine hydrochlorideand allyl 2-propene-1-thiolsulfinate obtained from Allz'wm sativum.

EXAMPLE 2 Methyl methanethiolsulfinate CH3S-SCH3 4.9 g. of methyl disulfide is dissolved in about 300 ml. of carbon tetrachloride and the solution is cooled in an ice bath. To the chilled solution there is slowly added with stirring a solution of 10.2 g. of perphthalic acid in 300 m1. of carbon. tetrachloride. The reaction mixture is allowed to stand for about an hour at room temperature and is then washed with two 100 ml. portions of a 4% aqueous solution of sodium bicarbonate followed by a 50 ml. portion of water. The carbon tetrachloride is then distilled from the carbon tetrachloride solution at about 30-40 mm. pressure and the distillation residue is subjected to fractional distillation at low pressure. The fraction which distills from the mixture at 48 C. at 0.3-0.5 mm. pressure consists of methyl methanethiolsulfinate. The yield is 1.15 g. The pure compound has a 124 of 1.222 and 11 1.548. Itis very soluble in water. Analysis calcd. for

CzI-IeOSzrC, 21.80%; H, 5.49%. Found: C, 22.06%; H, 5.78%.

EXAlVIPLE 3 Ethyl ethanethiolsulfinate 12.2 g. of ethyl disulfide is dissolved in 300 ml. of tertiary butyl alcohol and to this solution there is added with stirring during a period of about 5-10 minutes a solution of 12.8 g. of perfuoric acid in 500 ml. of tertiary butyl alcohol. The reaction mixture is allowed to stand for about an hour at room temperature and the tertiary butyl alcohol is then distilled from the solution at about 20 mm. pressure. The distillation residue is dissolved in chloroform and this solution is washed successively with a 150 ml. portion of 6% aqueous sodium bicarbonate solution and then with a 50 ml. portion of water- The chloroform is distilled from the chloroform solution at about 30-40 mm. pressure and the residue is' subjected to fractional distillation at low pressure. The fraction which distills from the mixture at 52 C. at 0.2-0.3 mm. pressure is ethyl ethanethiolsulflnate. The yield is 6.2 g. The pure compound has a 124 of 1.104 and n 1.524. It is soluble in water to -the extent of about 10%.

EXAMPLE 4 n-Prop'yl I-propanethiolsulfinate I CHa-CHs-CHr-S-S-CHr-CHi-CHa 4.50 g. of n-propyl disulfide is dissolved in 200 added with stirring during a period of about five minutes a solution of 6.50 g. of percamphoricacid in 100 ml. of acetonitrile. The reaction for about an hour and the acetonitrile is then distilled from the solution at about mm. pressure. The distillation residue is dissolved in chloroform and this solution is washed successively with two 50 ml. portions of a 3% aqueous solution of sodium bicarbonate and a 50 ml. portion of water. The chloroform is distilled from the chloroform solution at about 30-40 mm. pressure. The distillation residue is extracted successively with five 400 ml. portions of water and the combined aqueous extracts are extracted with two 100 ml. portions of chloroform. The chloroform is distilled from the chloroform solution at about -40 mm. pressure and the distillation residue is subjected to fractional distillation at low pressure. The fraction which distills from the mixture at 25 C. at 0.00'7-0.012 mm. pressure consists'of n-propyl l-propanethiolsulfinate. The yield is approximately 3.3 g. The pure compound has a (14 of 1.045 and 71 1.512. It is Analysis calcd. for CsH14OS2: C, 43.33%; 8.49%. Found: C, 43.50%; H, 8.43%.

EXAMPLE 5 n-Butyl I-butanethiolsulfinate 'orn-oHl-om-om-s-s-om-om-om-om 5.0 g. of n-butyl disulfide is dissolved in 300 ml.

of chloroform and the solution is cooled in an icebath. To the chilled solution there is added with stirring during a period of about five minutes a solution of 3.8 g. of perbenzoic acid in 60 ml. of

chloroform. The reaction mixture is allowed to stand at'room temperature for about an hourv and is then washed successively with two 50 ml. portions of a 3% aqueous solution of sodium bicarbonate and a 50 m1. portion of water. The chloroform is then distilled from the chloroform solution at about 30-40 mm. pressure and the distillation residue is subjected to fractional dis-.

7.0 g. of n-amyl disulfide is dissolved in 1000 ml. of petroleum ether and the solution is cooled in an ice-bath. To the chilled solution there is added with stirring during a period of about five minutes a solution of 4.7 g. .of perbenzoicacidin Analysis calcd. for 041610082: 0; 34.75%; H, 7.29%. Found: C, 35.06%; H, 7.46%.

ml. of acetonitrile and the solution is cooled inmixture is allowed to stand at room temperature soluble in water to the extent of about 2%.-

150 of petroleum ether; TheJreaction mix;

ture is-allowed to stand at room temperature for:

about an hour and is then washed successively with two 50 ml. portions of a 3% aqueous solution of sodium-bicarbonate-and a 50 m1. portion of water. The petroleum ether isthen. distilled from the petroleum ether solution at about 30-40 mm. pressure and thedistillation residue issulojected to fractional distillation at low pressure. The fraction which distills from the mix-"- ture at 45 C. at 10* ressure consists of n-amyl l-pentanethiolsulfinate. I he yield is approximately 4.26 g; The-pure com-- pound has a di of 0.980 and 70 1.499.- It issoluble to 0.0015% in water. Analysis oalcd. for Ciel-122032: C, 54.00%; H. 9.98%. Found; C, 54.03%; H-, 9.79%.

EXAMPLE 7 Tertiary butyl ethanethiolsulfinate In Example 5, when. there is used, instead oi the n-butyl disulfide, 4.? g. of ethyl tertiary butyl disulfide, there is obtained approximately 2.8g.

of tertiary butyl ethanethiolsulfinate, whichdistills from the reaction mixture at 3010. at 0.05- 0.10 mm. pressure. The pure compound has a 6141 of. 1.043 and 71 1.509. Analysis calcd. for

Col-114C528: c, 43.33%; H,-v 8.49%. Found: c.v 43.71%; H, 8.70%. I

By employing an oxidation-proceduresimilar to that shown in the above examples, there are. obtained 3-pyridinethyl 2-(beta-pyridyl) -1- ethanethiolsulfinate from b-isQZi-pyridinethyl). disulfide; benzyla1pha-toluenethiolsulfinate from benzyl disulfide; beta-carboxyethyl 2-carboxy-1- ethanethiolsulfinate from bisib'eta-carboxyethyl) disulfide; alpha, alpha-dimethyl-beta-aminobeta-carboxyethyl ethanethiolsulfinate from ethyl alpha, alpha-dimethyl-beta-amino-betacarboxyethyl disulfide; cyclohexyl cyclohexanethiolsulfinatefrom cyclohexyl clisulfide gammapiperidyl -piperidinethiolsulfinate from gamma piperidyl disulfide; gamma-tetrahydropyranyle 4-tetrahydropyranethiolsulfinate from. gamma tetrahydropyranyl 'disulfidep phenyl. benzenethiolsulfinate from phenyl :disulfide; mi-carhoxyphenyl 3-0arboxybenzenethiolsulfinate from his wherein: A: and? A. represent. alliyl: radicals, with;

. 0 .5- 2-.0:jn1olecular. equivalents of? anaorgani'c :pBr-

acid va-tpatemperature below-5.55" C. 2., The; processfior'preparing.an alkyl: alka-ne thiolsulflnate whichcomprises treating a; com-'- pound having, the formula.-

A '-S--S--A' wherein A ai'id- A represent alkyl radicals, with an approximately equirnolecular quantity of an organicper-acid at a. temperature below 55 C. in the presenceof an organic solvent.

3..1he process for preparingwbutyl l-bu'tanethiolsulfinate which comprises treating but'yl disulfide with an approximately equimol'ciilar quantity of perbenzoic acidin chloroform solution, ata temperaturebelow 55 C.

4. A compound having the formula AS-SA' wherein A and Af represent alkyl radicals.

- 5. Butyl l -butanethiolsulfinate, having the. formula CHsOHa'CHaUHz-S-S-CHaCHzCHaCHI and being characterizedby'havi-ng a d4 of 0.997 and n 1.506.

6. An organic thiolsulfinate having the formula wherein R and R are hydrocarbon radicals;

'sele'ctedfrom the group consisting of alkyl, ar

alkyl, and aryl radicals.

7. Ethyl. ethanethiolsulfinate,. having the formula oinwsav-cins andbeing characterized byhaving a @14 of 1.104' and 11 1.524. U

8'. Amyl l-pentane thiolsulfinate, having; the formula- CH -(C'H2)2x'CH'2'S SOHi-'(-CHi)ss and being characterized by having at (14 010983 and 71. 1.499.

9. The process which comprise treating an organic disulfide having the formulawhere R and R are hydrocarbon radicals, with 0.5-2.0 molecular equivalentsoi an organic peracid at a temperature below 55 C. and isolating the organic thiolsulfinatethus formed.

10. The process which comprises treating an organic disulfide having the formula RS--SR' Where Rand R are hydrocarbon radicals, Withan. approximately equimoleclllar amount of artoi'gan-ic per-acid I at a temperature below 5'5 G. inurepresence of air organic solvent,- and isolating the organic thio lsul -fir'iate thus formed:

GHESTEH J; CAVALLITO".

REFERENGES CITED The following referencesare of record the" file of this patent:

vollratheta-l.-: Proceedings-of Society for Experimental; Biology and Medicine, vol.- 36,: pages 55*58.

Glaseret a l-.: Archfiir" Exper. Path; und Bhar... vols-193, 1939, pagesl-9r Lehmann'z- Arch; 9 Exp. Path.- und- Phar.," vol. :14q ,*.-1 930;pages 2 i5-264r 

4. THE PROCESS FOR PREPARING AN ALKYL ALKANETHIOSULFINATE WHICH COMPRISES TREATING A COMPOUND HAVING THE FORMULA 